Two aspects of DNA damage and repair associated with malignant transformation are being studied in mouse cells and human fibroblasts, including cells from xeroderma pigmentosum (XP) patients and normal individuals. First, the biochemical mechanism responsible for the enhanced G2 radiosensitivity which characterizes the cultured fibroblasts of cancer-prone individuals and the malignant state is being investigated. To date, experiments measuring the kinetics of DNA strand-break repair of newly synthesized DNA from cells enriched in the G2 phase indicate that G2 radiosensitive cells either repair x-ray-induced DNA strand breaks more slowly than normal cells, or they acquire DNA strand breaks more rapidly than normal cells. These results were found comparing normal KD fibroblasts with the transformed derivative, Hut 24, and with glioblastoma cells, Wilm's tumor cells, and nontumorigenic fibroblasts from a retinoblastoma patient versus normal human skin fibroblasts. The second aspect of DNA damage and repair concerns the mechanisms involved in repair of DNA-protein cross-links induced with trans-platinum(II) diaminedichloride. Numerous and varied carcinogenic agents induce DNA-protein cross-links, and, since they have been reported to lead to transformation of 3T3 and 10T-1/2 mouse cells, their mechanisms of repair and possible deficiencies are important. We previously showed that these lesions were repaired by a pathway in addition to the nucleotide excision mechanism and that cell cycling is necessary for activation of this pathway. We have now shown that not only is DNA replication, per se, not required for repair but that "loosening up" of the chromatin, one consequence of DNA replication events, is not associated with repair in either of two XP group A cell lines (XP12BE, XP2OS) or in mouse L1210 cells.